Elevated intratumoral immune inflammation prior to treatment is typically associated with better outcomes in hot tumors treated with immune checkpoint inhibitors (ICIs). However, we observed a paradox in pMMR/MSS locally advanced rectal cancer (LARC) patients, where a subset with elevated baseline immune inflammation exhibited worse outcomes after combined radiotherapy and ICI treatment compared with patients with minimal immune inflammation. To investigate this counterintuitive finding, we performed paired scRNA-seq and scTCR-seq on longitudinally collected samples, including tumor biopsies (pre-treatment, post-radiotherapy, and post-immunotherapy) and peripheral blood mononuclear cells (pre-treatment and post-immunotherapy), from 20 pMMR/MSS LARC patients treated with sequential radiotherapy and ICI therapy (NCT06493240). We propose the concept of clonal entrapment to explain this phenomenon. Specifically, our profiling results reveal that increased HLA-DQA2 expression in dendritic cells and upregulated GDF15 expression in treatment-resistant tumor cells correlate with the restricted expansion of novel tumor-reactive TCR clonotypes. Consequently, the immune response is limited primarily by pre-existing TCR clonotypes within the tumor, especially those partially expanded under chronic inflammation, leading to the expansion of TCR clonotypes derived mainly from pre-treatment CD8+ T cell pools following ICI therapy. By identifying this feature of the pMMR/MSS LARC microenvironment, our study provides a high-resolution framework for understanding resistance to sequential radiotherapy and ICI therapy.

Objective:To explore the effect of tumor deposit (TD) on the prognosis of patients with stage Ⅲ colon cancer after radical resection.Methods:The clinicopathological data of patients with stage Ⅲ colon cancer after radical surgery at the Department of Gastrointestinal Surgery, Peking University People's Hospital from Jan to Dec 2015 were analyzed collected. Clinicopathological characteristics such as tumor location, degree of differentiation, mismatch repair status, lymphatic and venous invasion, and preoperative CEA and CA19-9 levels were used to study the effect of TD on the postoperative survival of patients.Results:Among the 155 patients with stage Ⅲ colon cancer, 37 (23.9%) had tumor deposits. The incidence of tumor deposits was higher in patients with intravascular tumor thrombus and preoperative serum CA19-9 elevation ( χ2=9.567, P=0.002; χ2=11.561, P=0.003); Patients with tumor deposits had worse overall survival and disease-free survival than those without cancer nodules (OS: P=0.029, DFS: P=0.025). Multivariate COX analysis found that tumor deposit was an independent risk factor for postoperative overall survival and disease-free survival ( HR=1.990, 95% CI: 1.032-3.835, P=0.040; HR=2.416, 95% CI : 1.205-3.820, P=0.009). Conclusions:Tumor deposit is an independent risk factor affecting postoperative overall survival and disease-free survival in patients with stage Ⅲ colon cancer. For patients with lymph node metastasis, incorporating TD into TNM staging can more accurately predict the postoperative prognosis.

The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid (PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z' factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore, the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.

Neoadjuvant therapy has become a standard treatment for patients with locally advanced rectal cancer to achieve better prognostic outcomes. The response to treatment has been shown to correlate closely with the prognosis. However, current evaluation systems only provide coarse assessment on limited information, due to the lack of accurate and reproducible approach for quantitation of different types of responses. In this study, a novel stain-free, slide-free multimodal multiphoton microscopy imaging technique was applied to image rectal cancer tissues after neoadjuvant therapies with high resolution and contrast. Qualitative and quantitative evaluation of tumor, stromal, and inflammatory responses were demonstrated which are consistent with current tumor regression grading system using American Joint Committee on Cancer criteria, showing the great potential of such approach to build a more informative grading system for accurate and standardizable assessment of neoadjuvant therapy in rectal cancer.

Currently, research on intestinal diseases is mainly based on animal models and cell lines in monolayers. However, these models have drawbacks that limit scientific advances in this field. Three-dimensional (3D) culture systems named organoids are emerging as a reliable research tool for recapitulating the human intestinal epithelium and represent a unique platform for patient-specific drug testing. Intestinal organoids (IOs) are crypt–villus structures that can be derived from adult intestinal stem cells (ISCs), embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs) and have the potential to serve as a platform for individualized medicine and research. However, this emerging field has not been bibliometric summarized to date. Here, we performed a bibliometric analysis of the Web of Science Core Collection (WoSCC) database to evaluate 5,379 publications concerning the use of organoids; the studies were divided into four clusters associated with the current situation and future directions for the application of IOs. Based on the results of our bibliometric analysis of IO applications, we systematically summarized the latest advances and analyzed the limitations and prospects.

Objective:To observe the clinical characteristics of esophageal reflux after total gastrectomy (ERATG), and to explore the mechanism of occurrence.Methods:Fourteen gastric cancer patients who underwent total gastrectomy were prospectively enrolled in this study. The postoperative symptoms were observed and recorded and 24 h MII-pH with pH monitoring was performed to investigate the characteristics of postoperative reflux.Results:After total gastrectomy patients were with different degrees of ERATG as heartburn, appetite loss, chest tightness and belching. The overall nature of ERATG is mainly weak acid, with a pH between 4 and 7. ERATG involved esophageal-jejunal anastomosis and a length of esophagus 7 cm above the anastomosis. Patients with typical reflux symptoms had a lower pH minimum in the upright position than those without typical symptoms[(4.76±0.71) vs.(5.68±0.37), t=2.866, P<0.05]. Patients with typical reflux symptoms had a higher frequency of reflux of mixed liquid and liquid-air reflux than those without typical symptoms[liquid(31.25±29.76) vs.(4.50±9.14), t=0.011, P<0.05; liquid-air(19.50±12.99) vs.(2.00±2.61), t=0.004, P<0.05]. Conclusion:ERATG is mainly a upward reflux of weakly acidic gas, with typical symptoms of heartburn, appetite loss, chest tightness and belching. Patients with typical symptoms usually have lower pH in the upright position.

: Hemophagocytic lymphohistiocytosis (HLH) comprises a group of severe immune function disorders that can lead to immune-mediated organ damage. There are two subtypes of HLH: primary and secondary. Secondary HLH is associated with infectious, oncologic, chemotherapeutic, and other underlying causes, and studies on HLH triggered by tumors have mainly focused on hematological malignancies. Secondary HLH in patients with solid tumors is rare. Here, we present two cases of gastric cancer complicated with HLH. The patient 1 was diagnosed as gastric cancer at stage I and got intractable fever after a distal subtotal gastrectomy without any evidence of infections or other complications. The patient 2 suffered from unresectable gastric adenocarcinoma and got fever, hemorrhagic rashes, and petechiae in mouth after six cycles of neoadjuvant chemotherapy. After detailed and comprehensive examinations, HLH was diagnosed in the two patients according to 2004 HLH diagnostic criteria, and the patients received treatment including immunosuppressive agents immediately. After therapy, the two patients showed partial remission, but both eventually died due to HLH relapse or progression of the primary tumor. The treatment regimen for HLH is intricate, and only a few relevant studies have focused on the treatment of cancer patients with HLH. The high mortality associated with this disease calls for more attention and additional research to improve the prognosis for these patients.

Sexual dysfunction with the incidence of 5%-90% is a common postoperative complication of rectal cancer and the ratio of men and women is similar. Sexual function is innervated by the abdominal-pelvic autonomic nerve. Different sexual dysfunctions can be caused by different parts and degrees of injury in autonomic nerve during operations of rectal cancer. With the development of pelvic autonomic nerves preservation in rectal cancer radical resection, postoperative sexual function can be protected. There may be many factors increasing the incidence of postoperative sexual dysfunction in rectal cancer, such as postoperative psychological factors, stoma, abdominal-perineal resection and radiotherapy. The effects of laparoscopic surgery, robotic surgery, transanal total mesorectal excision and lateral lymph node dissection on postoperative sexual function remain controversial. Based on the multidisciplinary cooperation model, attention should be paid to psychological intervention of patients and their partners. In clinical practice, for male using phosphodiesterase-5 inhibitors, vacuum erectile devices, injection of vasodilators through the penis or urethra, and for female local application of estrogen and lubricants in the vagina are effective treatment for postoperative sexual dysfunction of rectal cancer. In addition, stem cell therapy has a promising prospect for sexual dysfunction.

Objective Recent studies have shown that tumor-associated macrophages (TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer (GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified. Methods THP-1 monocytes were induced by PMA/interleukin (IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation (ChIP) assay were used to investigate the mechanism of transforming growth factor β2 (TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo. Results We found that Kindlin-2 expression was upregulated at both mRNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo. Conclusions This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.

Objective: The aim of the study was to evaluate the oncological outcomes of complete mesocolic excision (CME) in colon cancer patients. Summary Background Data: CME is considered a standard procedure for colon cancer patients. However, previous evidence regarding the effect of CME on prognosis has fundamental limitations that prevent it from being fully accepted. Methods: Patients who underwent radical resection for colon cancer were enrolled between November 2012 and March 2016. According to the principles of CME, patients were stratified into 2 groups based on intraoperative surgical fields and specimen photographs. The primary outcome was local recurrence-free survival (LRFS). The clinicopathological data and follow-up information were collected and recorded. The final follow-up date was April 2016. The trial was registered in ClinicalTrials.gov (identifier: NCT01724775). Results: There were 220 patients in the CME group and 110 patients in the noncomplete mesocolic excision (NCME) group. Baseline characteristics were well balanced. Compared with NCME, CME was associated with a greater number of total lymph nodes (24 vs 20, P = 0.002). Postoperative complications did not differ between the 2 groups. CME had a positive effect on LRFS compared with NCME (100.0% vs 90.2%, log-rank P < 0.001). Mesocolic dissection (100.0% vs 87.9%, log-rank P < 0.001) and nontumor deposits (97.2% vs 91.6%, log-rank P < 0.022) were also associated with improved LRFS. Conclusions: Our findings demonstrate that, compared with NCME, CME improves 3-year LRFS without increasing surgical risks.

Objective To investigate the influence of mismatch repair status on clinicopathological characteristics and prognosis in patients with colon cancer.Methods Patients who underwent radical excision for colon cancer between Nov 2012 and Mar 2016 at Peking University People's Hospital were enrolled.Clinicopathological data and prognosis were collected.Multivariate analysis were used to identify independent characteristics of MMR-deficient colon cancer.The influence of MMR-deficient on prognosis of colon cancer were analyzed through Kaplan-Meier curve.Results The overall rate of MMR-deficient in colon cancer was 17.1％ (51/299).Multivariate logistic regression analysis showed that low differentiation (OR =3.555,95％ CI:1.685-7.640,P ＜ 0.001),right-sided colon cancer (OR =5.645,95％ CI:2.483-14.715,P ＜ 0.001) and UICC Stage Ⅰ-Ⅱ (OR =4.099,95％ CI:1.863-9.840,P ＜0.001) were associated with MMR-deficient colon cancer.Conclusion Low differentiation,right-sided colon cancer and UICC Stage Ⅰ-Ⅱ were more common in MMR-deficient colon cancer.

Objecetive To investigate the ability of extramural vascular invasion(EMVI) in predicting 3-years disease-free survival(3yr DFS)of patients with colon cancer. Methods Between February 2009 and December 2013, patients who had histologically proven primary colon cancer and underwent curative resection were included in this retrospective study. EMVI was defined as tumor tissue in adjacent vessels beyond colon wall on MDCT. DFS was defined as the time from the date of curative resection to the date of local recurrence,and/or distant disease,or tumor-related death. Univariate and multivariate analysis were conducted to identify prognostic factors associated with 3yr DFS. Kaplan-Meier analyses were used to compare 3yr DFS. Cox’s proportional hazards models were used to measure the impact of confounding variables on survival rates. Chi-square test was used to analyze the difference of recurrent/metastatic rate. Results In final,90 patients were included in this study that were identified as stageⅢpatients by pathology based on American Joint Committee on Cancer (AJCC). Multivariate analysis showed that elevated serum CA19-9(HR=2.229,95%CI 1.040-4.776,P=0.039)and EMVI positive(HR=3.266,95%CI 1.648-7.173,P=0.003) were identified as independent predictors of 3yr DFS in stageⅢcolon cancer. Cumulative 3-year DFS were 52.8%and 81.5%(95%CI 1.648-7.173)for EMVI positive and negative patients,and 55.6%and 76.6%(95%CI 1.040-4.776)for elevated serum CA19-9 and normal serum CA19-9,significances were seen (P<0.05). Compared with ctEMVI positive combined with elevated serum CA19-9,3yr recurrent/metastatic rate of ctEMVI negative combined with normal serum CA19-9 was lowerer significantly (10.5%vs. 54.5%,P<0.05).Conclusion EMVI detected with ceMDCT, and elevated serum CA19-9 level could be used as independent predictors of 3yr DFS in patients with stageⅢ colon cancer.

Objective To investigate the association between extramural vascular invasion (EMVI) detected by multi-detectors computed tomography (MDCT) with contrast enhanced (ceMDCT) and clinicopathologic characteristics in patients with colon cancer.Methods Between February 2009 and December 2013,patients with histologically proven primary colon cancer and undergoing curative resection were included in this retrospective study.According to American Joint Committee on Cancer TNM staging system,patients of stage Ⅱ and Ⅲ were included in this study.EMVI status detected by MDCT (ctEMVI) was defined according to the EMVI scores.Chi-square test was used to analyze the association between clinicopathologic characteristics and ctEMVI.Results 165 stage Ⅱ and stage Ⅲ patients were included in this study as confirmed by pathology based on AJCC.Positive ctEMVI was demonstrated in 51 patients (34.5％,51/165).There were significant association between positive ctEMVI and age ＜ 65 years (x2 =4.810,P =0.031),ceMDCT defined tumor stage (x2 =17.911,P =0.000),ceMDCT defined metastatic lymph node (x2 =5.436,P =0.022),tumor size≥5 cm (x2 =3.799,P =0.036) and pathological T stage (x2 =13.346,P =0.001).Conclusions EMVI,detected by ceMDCT,is significantly associated with age,tumor size and T staging in colon cancer.

BACKGROUND:Extramural Vascular Invasion (EMVI) is histologically defined as the presence of tumor cells beyond the muscularis propria in vessels resulting in disease metastases.OBJECTIVE:To determine whether EMVI, detected by contrast-enhanced multiple-row detectors computed tomography (MDCT), has closely association with synchronous metastases in colon cancer.METHODS:Patients with pathology proven colon cancer were included in this retrospective study. Preoperative imaging status, including Extramural tumor depth, Lymph nodes, tumor location, and ctEMVI status, were defined on MDCT. Postoperative pathological tumor stage, lymph node stage, and tumor differentiation, were defined in accordance with the American Joint Committee on Cancer (AJCC) 7th Edition. Synchronous metastases were detected on follow-up MDCT 3 months after initial diagnosis or by surgery, if available. Associations between ctEMVI and other preoperative and postoperative factors were analyzed using Chi-squared tests. Logistic regression analyses were performed to analyze the preoperative and postoperative factors of synchronous metastases in colon cancer.RESULTS:ctEMVI was observed in 96 patients (96/241, 39.8%). The presence of ctEMVI varied significantly depending on ctEMD (χ2 = 66.557, P<0.001), lymph nodes status on MDCT (χ2 =24.533, P=0.001), pathological tumor status (χ2 = 36.267, P <0.001) and pathological lymph nodes status analyses (χ2 =32.103, P <0.001). Synchronous metastases were seen in 36 patients (36/96, 37.5%) with ctEMVI and 11 (11/145, 7.6%) patients without ctEMVI. The incidence of synchronous metastases was significantly higher in the cohort of positive ctEMVI with odds ratio (OR) of 7.309 (95% CI 3.485∼15.330, P<0.001). Positive ctEMVI (Odds ratio 4.654, 95%CI: 1.987∼10.898, P <0.001) and ctEMD larger than 5 mm (Odds ratio 2.654, 95%CI: 1.116∼6.309, P =0.027) were demonstrated to be significant preoperative factors in predicting synchronous metastases.CONCLUSION:MDCT-detected EMVI could be used as a preoperative factor to predict synchronous metastases in colon cancer.

AIM:To compare disease-free survival (DFS) between extramural vascular invasion (EMVI)-positive and -negative colon cancer patients evaluated by computed tomography (CT).METHODS:Colon cancer patients (n = 194) undergoing curative surgery between January 2009 and December 2013 were included. Each patient's demographics, cancer characteristics, EMVI status, pathological status and survival outcomes were recorded. All included patients had been routinely monitored until December 2015. EMVI was defined as tumor tissue within adjacent vessels beyond the colon wall as seen on enhanced CT. Disease recurrence was defined as metachronous metastases, local recurrence, or death due to colon cancer. Kaplan-Meier analyses were used to compare DFS between the EMVI-positive and -negative groups. Cox's proportional hazards models were used to measure the impact of confounding variables on survival rates.RESULTS:EMVI was observed on CT (ctEMVI) in 60 patients (30.9%, 60/194). One year after surgery, there was no statistically significant difference regarding the rates of progressive events between EMVI-positive and -negative patients [11.7% (7/60) and 6.7% (9/134), respectively; P = 0.266]. At the study endpoint, the EMVI-positive patients had significantly more progressive events than the EMVI-negative patients [43.3% (26/60) and 14.9% (20/134), respectively; odds ratio = 4.4, P < 0.001]. Based on the Kaplan-Meier method, the cumulative 1-year DFS rates were 86.7% (95%CI: 82.3-91.1) and 92.4% (95%CI: 90.1-94.7) for EMVI-positive and EMVI-negative patients, respectively. The cumulative 3-year DFS rates were 49.5% (95%CI: 42.1-56.9) and 85.8% (95%CI: 82.6-89.0), respectively. Cox proportional hazards regression analysis revealed that ctEMVI was an independent predictor of DFS with a hazard ratio of 2.15 (95%CI: 1.12-4.14, P = 0.023).CONCLUSION:ctEMVI may be helpful when evaluating disease progression in colon cancer patients.

Objective To evaluate preoperative staging by multidetector computed tomography (MDCT) for nonperitonealized colon cancer.Methods From January 2009 to December 2014,97 staging Ⅱ A nonperitonealized colon cancer patients at the Department of General Surgery,Peking University People's Hospital were enrolled in the study.Radiological T staging was evaluated through preoperative MDCT and statistical analysis was performed to evaluate the prognosis of different stages.Results There were 1 case of T2 stage,33 cases of T3 stage and 63 cases of T4 stage.Patients with radiological T3 and T4stages had significantly different survivals (x2 =9.174,P =0.002).According to the imaging standards,tumor invasion depth (extramural tumor depth,EMD) was estimated as 13 cases of EMD ＜ 1 mm,31 cases of1 mm≤EMD≤5 mm,39 cases of 5 mm＜EMD＜15 mm,14 cases ofEMD＞15 mm.The 3 year's disease-free survival was significantly different between groups of EMD 1-5 mm and 5-15 mm (x2 =4.549,P =0.033).The 5-year overall survival was also significantly different (x2 =10.315,P =0.001).Multi-variate analysis showed radiological T staging (RR =5.919,95％ CI:1.301-26.933,P =0.021) and EMD (RR =8.001,95％ CI:1.657-38.664,P =0.010) were independent prognostic factors.Conclusions MDCT can make pre-operative staging for the nonperitonealized colon cancer and this radiological T staging and EMD are independent poor prognostic factors in colonic neoplasms.

目的 探讨右半结肠癌淋巴结转移规律.方法 前瞻性入组2012年10月至2014年12月在北京大学人民医院行完整结肠系膜切除(CME)的病人,按照日本《大肠癌诊疗规范》(第7版)进行淋巴结分站取材和病理学检查,分析阳性淋巴结分布规律、影响淋巴结转移的临床病理因素.结果 右半结肠癌肠旁、中间、中央淋巴结转移发生率分别33.0％、18.3％、16.5％ (P=0.005),肠旁淋巴结转移主要位于距离肿瘤＜10 cm以内组织,但是＞10 cm组织(1.7％)仍有淋巴结转移.淋巴结转移发生率与肿瘤T分期和分化程度有关.T3～T4期病人淋巴结转移发生率,高于T1～T2期(46.2％ vs.9.1％,P＜0.05).低分化及未分化癌淋巴结转移发生率为64.7％,明显高于高分化癌(0)、中分化癌(36.0％),P＜ 0.05,且分化程度越差更易出现肠旁及中央淋巴结转移.幽门下组淋巴结转移发生率为2.6％(3/115),且均为结肠肝曲癌.14.8％(17/115)的病人出现跳跃性淋巴结转移.结论 右半结肠癌淋巴结转移存在于肠旁、中间、根部系膜组织,术中应常规清扫,结肠肝曲癌还应清扫幽门下淋巴结,CME有助于彻底清扫该区域淋巴结.